Homozygous mutations in a predicted endonuclease are a novel cause of congenital dyserythropoietic anemia type I

The congenital dyserythropoietic anemias are a heterogeneous group of rare disorders primarily affecting erythropoiesis with characteristic morphological abnormalities and a block in erythroid maturation. Mutations in the CDAN4 gene, which encodes Codanin-1, underlie the majority of congenital dyserythropoietic anemia type I cases. However, no likely pathogenic CDAN4 mutation has been detected in approximately 20% of cases, suggesting the presence of at least one other locus. We used whole genome sequencing and segregation analysis to identify a homozygous T to A transversion (c.533T>A), predicted to lead to a p.L178Q missense substitution in C150RF41, a gene of unknown function, in a consanguineous pedigree of Middle-Eastern origin. Sequencing C150RF44 in other CDAN4 mutation-negative congenital dyserythropoietic anemia type I pedigrees identified a homozygous transition (c.281A>G), predicted to lead to a p. Y94C substitution, in two further pedigrees of South-East Asian origin. The haplotype surrounding the c.281A>G change suggests a founder effect for this mutation in Pakistan. Detailed sequence similarity searches indicate that C150RF41 encodes a novel restriction endonuclease that is a member of the Holliday junction resolvase family of proteins.